CN1165519A - Process for purifying and isolating 2'-deoxy-2'-2'-difluoronucleosides - Google Patents
Process for purifying and isolating 2'-deoxy-2'-2'-difluoronucleosides Download PDFInfo
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- CN1165519A CN1165519A CN95196272A CN95196272A CN1165519A CN 1165519 A CN1165519 A CN 1165519A CN 95196272 A CN95196272 A CN 95196272A CN 95196272 A CN95196272 A CN 95196272A CN 1165519 A CN1165519 A CN 1165519A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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Abstract
A process to purify and isolate a beta-anomer enriched nucleoside comprising: a) providing a mixture containing R'' and a beta-anomer enriched nucleoside of formula (IB), wherein each X is independently selected from hydroxy protecting groups and R' is a nucleobase of formula (II), where W is an amino protecting groups; and R'' is a nucleobase of formula (III), where W' is an amino protecting group or hydrogen; in a high boiling solvent; b) diluting the mixture with an organic solvent from the group consisting of ethers, esters and nitriles; c) adding the diluted reaction mixture to aqueous acid; and d) holding the acid mixture so prepared at a temperature from 70 DEG C to 100 DEG C until the product of formula (IB), where W is now W', has precipitated.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, the invention provides a kind of purification and separate 2 '-deoxidation-2 ', 2 '-method of Difluoronucleosides.
Background technology
For Synthetic 2 '-the continual interest of deoxynucleoside and analogue aspect thereof be reflected in they aspect virus disease and the cancer as the successful Application of therapeutical agent.Whole 2 '-building-up process of deoxynucleoside in a crucial step be exactly to purify and the β anomer that separates needed nucleosides.Why key be because Synthetic 2 '-method of deoxynucleoside generally is not stereospecific, its formation be the mixture of α nucleosides and beta nucleoside.
Wo Bulugen (Vorbruggen) etc. at " organic chemistry magazine " (J.Org.Chem), 41, in 2084 (1976), lotus not (M.Hofer) at " GDCh's will " (Chem.Ber,) 93,2777 (1960), Wo Ke (Walker) etc. are at " nucleic acids research " (Nucleic Acid Research), and 12,6827 (1984), prop up (R.P.Hodge) etc. suddenly at " organic chemistry magazine ", in 56,1553 (1991), wingceltis (Tann) etc. are at " organic chemistry magazine " 50, in 3644 (1985), Huo Weier (Howell) etc. are in " organic chemistry magazine " 53,85 (1988), and week people such as (Chou) is in US patent 4, all reported the whole bag of tricks of synthetic deoxynucleoside α anomer and the anomeric mixture of β in 965,374.
Although the method for synthetic nucleosides obtains many progress, but need always a kind of method can with higher productive rate purify effectively with separate be rich in β-anomeric 2 '-deoxidation-2 ', 2 '-Difluoronucleosides, Difluoronucleosides wherein is not have synthetic in the presence of the catalyzer.
Therefore, the purpose of this invention is to provide a kind of purify effectively with separate be rich in β-anomeric 2 '-deoxidation-2 ', 2 '-method of Difluoronucleosides.
By following narration to embodiment, other purpose of the present invention and advantage are with self-evident.
Detailed Description Of The Invention
The present invention is a kind of purification and separate the method that is rich in β-anomeric nucleosides, and it comprises following each step:
A) provide and contain R " and as shown in the formula be rich in the β-mixture of anomeric nucleosides in a kind of high boiling solvent,
Each X is independently selected from hydroxyl protecting group in the formula, R ' be as shown in the formula nuclear alkali:
Wherein W is an amino protecting group, and R " be as shown in the formula nuclear alkali,
Wherein W ' is amino protecting group or hydrogen;
B) with this mixture of organic solvent diluting that is selected from ether, ester and nitrile;
C) reaction mixture with dilution is added in the aqueous acid, and
D) acidic mixture that will so make remains on 70-100 ℃, and up to being settled out formula IB product, wherein W is W '.
Implement preferred plan of the present invention
Except as otherwise noted, all temperature all are degree centigrade in presents, and all umbers, percentage ratio etc. all are by weight, and all mixtures all are by volumes.The anomer mixture is represented with w/w ratio or per-cent.The aliphatic alkyl of the straight chain, ring-type or the side chain that are no more than 7 carbon atoms represented preferably to contain in term " alkyl " when being used in combination separately or with other speech, aliphatic hydrocarbyl as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl, n-hexyl, 3-methyl amyl etc. or the straight chain, ring-type or the side chain that replace, as chloroethyl, 1,2-Dichloroethyl etc.Term " replacement " separately or represent to be replaced by one or more cyano group, halogen, carbalkoxy, toluoyl, nitro, alkoxyl group, alkyl and dialkyl amidos of being selected from when being used in combination." it is anomeric to be rich in certain " separately or represent that wherein specific anomeric ratio greater than 1: 1 anomeric mixture, can comprise the anomer of substantially pure when being used in combination.
Hydroxyl protecting group (X) refers to hydroxyl protecting group known in the prior art; as " protecting group in the organic chemistry " version the 3rd Zhanghe Green (Green) work in 1973 of publishing in Mike's rice difficult to understand (Mc Omie) editor Plenum press (New York); John, the group described in " protecting group in the organic synthesis " chapter 2 that J.Wiley and Sons (New York) (1981) press publishes.Preferred hydroxyl protecting group is into ester group, such as ethanoyl, propionyl, butyryl radicals, valeryl, 2-chloracetyl, benzoyl, the benzoyl of replacement, carbobenzoxy, the methoxyl group ethanoyl of formyl radical, ethanoyl, replacement; Carbonic acid ester derivative is such as carbobenzoxy, ethoxycarbonyl, tertbutyloxycarbonyl, vinyl oxygen carbonyl, 2,2,2-trichloro-ethoxycarbonyl and carbobenzoxy-(Cbz); Become alkyl ether groups, as phenmethyl, diphenyl methyl, trityl group, the tertiary butyl, methoxymethyl, THP trtrahydropyranyl, allyl group, tetrahydro-thienyl, 2-methoxy ethoxy methyl; Carbamate is as N-phenylcarbamate and TMSIM N imidazole aminocarbamic acid ester; More preferably benzoyl, mono-substituted benzoyl and disubstituted benzenes formyl radical, ethanoyl, valeryl, trityl group ether, most preferably benzoyl.
Amino protecting group (W) is selected from into the silyl amine groups, as trialkylsilkl, comprises trimethyl silyl; Sec.-propyl dialkyl group silyl, alkyl di-isopropyl silyl, triisopropyl silyl, 1,1,3,3-tetra isopropyl disiloxane base, tertiary butyl dialkyl group silyl and tertiary butyl diaryl silyl; Carbamate is as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 4-methoxyl group benzyloxy carbonyl and 4-nitro carbobenzoxy-(Cbz); Formyl radical, ethanoyl, benzoyl and valeryl amino; Become ether group, as methoxymethyl, the tertiary butyl, benzyl, allyl group and THP trtrahydropyranyl; Preferred ammonia protecting group is a trimethyl silyl.
The first step of the inventive method provides and contain R in a kind of high boiling solvent " and be rich in β-anomeric mixture as shown in the formula nucleosides:
Wherein each X is independently selected from hydroxyl protecting group, R ' be as shown in the formula nuclear alkali,
Wherein W is an amino protecting group, and
R " be as shown in the formula nuclear alkali,
Wherein W ' is amino protecting group or hydrogen.
Can prepare such mixture with many kinds of diverse ways.At european patent application No93304817, narrated the method for synthetic this mixture and claimed in 5.Use is at european patent application No.93304817, and following some method of narration in 5 is (without catalyzer, " examine alkali, the P9 of EP 93304817,5 with excessive R; Use high boiling solvent, P10,13～17 row) can prepare α-anomer and β-anomer than greater than be less than or equal at 1: 11: 9 be rich in β-anomeric nucleosides.Must use excessive a lot of R " to obtain this ratio.By method of the present invention excessive R " is separated with required product.
High boiling solvent is that boiling point is higher than 70 ℃ solvent.This high boiling solvent polarity is moderate, and is stable and be non-nucleophilic to acid.Typical high boiling solvent is halogenated aromatic alkyl, alkoxyl group and the aromatic solvent of halogen replacement and their mixture.Preferred high boiling solvent is 1,2-ethylene dichloride, 1,1,2-trichloroethane, glyme, diglyme, toluene, dimethylbenzene, methyl-phenoxide, two methyl chlorobromides, chlorobenzene, two bromochloromethanes, methenyl bromide, methylene bromide, acetonitrile, propionitrile, diox and their mixture, most preferably methyl-phenoxide.
Contain R in case provide " and the mixture of the described β of being rich in anomer nucleosides, the inventive method is then carried out as follows.At first, be higher than this reaction mixture of organic solvent diluting of 60 ℃ with boiling point.Acceptable solvent has ethers, ester class and nitrile; Preferred example is acetonitrile, ethyl acetate and tetrahydrofuran (THF).Can under the high temperature of temperature of reaction, dilute.Organic solvent should be heated to high temperature, and the temperature of reaction mixture and solvent all should be between 70～110 ℃.Most preferred solvent is an acetonitrile.
The amount of the organic solvent that adds is the R that every gram uses, and " (protected or not protected cytosine(Cyt)) is with 1～5ml solvent.Behind diluted reaction mixture, need not special retention period, the mixture of dilution can be carried out next step immediately.The reaction mixture of dilution is added in a large amount of aqueous acids at high temperature.The purpose of this aqueous acids is the excessive R of dissolving, and " (protected or unprotected cytosine(Cyt)) just uses this acid in the 9th page of described glycyl reaction of EP application No 93304817,5.Therefore, the quantity of aqueous acids and acidity depend on R " the excessive degree of (protected or unprotected cytosine(Cyt)) that reaction itself is used.Have, the quantity of aqueous acids also depends on the selection situation of the acidic substance that use in preparation aqueous acids process again.
Most preferred acid is to use concentration 1～6N, the hydrochloric acid of preferred 4N.When using this acid, excessive R " (protected and unprotected cytosine(Cyt)) is 5 times to 20 times, and the amount of aqueous hydrochloric acid is the R of every gram use " (protected or not protected cytosine(Cyt)) is with 3～5ml hydrochloric acid.
Yet other aqueous inorganic acid and condition also are available, and can carry out preferred under varying environment.For example mineral acid such as sulfuric acid, sulfurous acid, phosphoric acid, nitric acid and phosphonic acids are if the operator needs also can use.The concentration of acid can change in wide range, but roughly is inversely proportional to the receiving amount of whole separating step.In general, can use the concentration of 1N～10% in aqueous acids.For various acid and the consumption in reaction mixture, optimize the consumption of aqueous acids by experiment.Required experiment is very simple, only requires that the operator regulates sour concentration and consumption successively according to the specific reaction mixture that uses, and " solubleness of (protected or not protected cytosine(Cyt)) gets final product to observe R in all cases.
When lumping together, aqueous acids and reaction mixture need not heating.Aqueous acids can be in envrionment temperature, as long as the mixture for preparing is warming to 70～100 ℃ temperature.Reaction heat can make mixture reach this temperature completely, and heated mixt also needs outside in some cases.In some cases, reaction heat can make temperature of charge surpass 100 ℃, so must reaction mixture make it to be parked in below 100 ℃.Why like this, be because the aqueous acids temperature can not too highly be very important, otherwise can be decomposed prematurely in any protecting group of this stage of present method.When using acetonitrile as organic solvent, the highest preferred temperature is 70～80 ℃.
The acidic mixture that adds the reaction mixture of dilution and produce in aqueous acids is preferably in the appropriateness stirring and keeps for some time down.The physical change that is taken place in this maintenance phase is excessive R, and " (protected or not protected cytosine(Cyt)) is dissolved in the aqueous acids layer, and required beta-nucleosides is precipitated out.This precipitation is selectively, and unwanted α nucleosides then major part is stayed in the organic layer.Therefore, acidic mixture must be kept under constant temperature until this two physical changes occurring.In general, be suitable from 10 minutes to 1 hour during this period of time.
Through after enough hold-times, by filter or centrifugal with the beta nucleoside that is precipitated out from two liquid phase separation, wash with aqueous acids again.Should filter under suitable steady temperature or centrifugal, " (protected or unprotected cytosine(Cyt)) is precipitated out from solution to prevent dissolved R.Beta-nucleosides with this method separation and purification still can have amino protecting group (W), and perhaps amino protecting group (W) also can be dissociated and be replaced by the H atom.With aforesaid method separate and the beta-nucleosides of purifying " (protected or unprotected cytosine(Cyt)) and other impurity are very pure, find that also the required compound for preparing like this has very high productive rate with regard to α-nucleosides, R.
When acidic mixture is filtered or centrifugal when removing solid product, the organic layer of filtrate has just separated with water layer.Excessive R " can remove from this layer and recycle in method in water layer by (protected or unprotected cytosine(Cyt)).Can be simply by " (protected or unprotected cytosine(Cyt)) filters; perhaps with the water layer alkalization, cools off this basic solution and the filtration R " methods such as (protected or unprotected cytosine(Cyt)s) reclaims R " (protected or unprotected cytosine(Cyt)) with collecting precipitation with the water layer cooling and with the R that is precipitated out.The cytosine(Cyt) that reclaims from aforesaid method is recycled to the No.93304817 as EP termly, in the method for the manufacturing mixture described in 5.Like this, method of the present invention has just guaranteed R, and " (protected or unprotected cytosine(Cyt)) can circulate economically, and this is a useful performance of present method.
The final step of present method is from remove protecting group X and the residual W of possibility through the protected solid type IB nucleosides of purifying.By removing the not protection nucleosides that protecting group obtains having same anomer ratio.
Use proton type solvent ratio such as water or alcohol to be easy to branch and take off most of silyl amino protecting group.With process that mineral acid contacts in, most of silyl amino protecting groups are vulnerable and decompose.Under 0～100 ℃ temperature, be hydrolyzed and remove acyl group protecting group and acyl amino protecting group as benzoyl with highly basic.The highly basic or the middle highly basic that are suitable for using in this reaction are that its pKa (at 25 ℃) value is 8.5～20.0 alkali.Such alkali comprises alkali metal hydroxide such as NaOH or KOH; Alkali metal alcoholates such as sodium methylate or potassium tert.-butoxide; Alkali metal ammonia compound; Amine such as diethylamine, azanol, ammonia etc. and other conventional base such as hydrazine etc.Need at least 1 normal alkali for each protecting group.
Also can remove the acyl group protecting group with acid catalyst such as methylsulfonic acid, hydrochloric acid, Hydrogen bromide, sulfuric acid or with acidic ion exchange resin.Be preferably in than under the higher temperature, such as carrying out such hydrolysis under the reflux temperature of mixture, but strong especially when sour when using, also can use low temperature to envrionment temperature.Must preserve these acyl group protecting groups carefully, make them can premature decomposition in the early stage of the inventive method.
Use currently known methods, for example, remove the ether protecting group with sulfur alcohol and aluminum chloride.
The t-butyldimethylsilyl protecting group requires acidic conditions, such as contacting with the gas hydrogen halide it is removed.
Generally can particularly carry out the removal of blocking group in water-based alkanol such as the methyl alcohol at alcoholic solvent.Yet, also can in any habitual solvent, carry out deprotection reaction, such as at polyvalent alcohol such as ethylene glycol, ethers such as tetrahydrofuran (THF), ketone such as acetone and methylethylketone, or in the methyl-sulphoxide.
In a preferred embodiment, deprotection reaction has used ammonia to remove the benzoyl hydroxyl protecting group under 10 ℃.Yet, in this reaction, preferably use excessive alkali, though use the quantity of excess base also non-key.
Can be used in US P4, in 965,374 the method for narration from reaction mixture, extract and/or isolate as shown in the formula obtain be rich in β-anomeric nucleosides or its organic acid or inorganic acid addition salt.
Following embodiment illustrates concrete aspect of the present invention, and limits the scope of the invention never in any form, also should so not explain.
Embodiment 1
With the preparation of 22.5 normal two (trimethyl silyl) cytosine(Cyt), purification and separate be rich in β-anomeric 1-(2 '-deoxidation-2 ', 2 '-two fluoro-3 ', 52-two-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidine-2-ketone
In the 250ml three-necked bottle, add 30g cytosine(Cyt), 25mg ammonium sulfate and 150ml hexamethyldisilazane,, all dissolve the back at all solids and kept 30 minutes mixture heating up to 125 ℃.Temperature is risen to 145 ℃ then, keep, at breaking of vacuum to 120 ℃, begin to form solid then until liquid level upper strata in bottle up to stopping boiling.Mixture is cooled to 105 ℃ then, adds the 25ml methyl-phenoxide.
In another one 125ml flask with 10ml methyl-phenoxide and 5.75g 2-deoxidation-2,2-two fluoro-3,5-dibenzoyl-D-ribofuranosyl-1-α-methanesulfonates mixes, heated mixt is until forming homogeneous liquid.Under constant temperature, this liquid is added in the cytosine(Cyt) mixture, and the mixture after will merging kept 24 hours at 100 ℃.
The 4N hydrochloric acid of 133ml portion is placed in the 500ml flask.The a acetonitrile of 31.3ml is added in the reaction mixture, along with constant stirs, the reaction mixture of dilution is poured in the acid then, simultaneously cooling bath is used for this 500ml flask.The mixture that stirring merges under 70 ℃ 10 minutes filters under constant temperature then.With 25ml 4N hydrochloric acid the wet cake pulp was also filtered in 10 minutes once more down at 70 ℃.70 ℃ with the 25ml deionized water with the pulp 10 minutes again of this filter cake, filter, wet cake again at 70 ℃ with the pulp of 50ml deionized water.Use NaHCO
3The pH value of water slurry is transferred to 7,, filters once more at 50 ℃ or higher with mixture stirring 10 minutes.Once more 70 ℃ with the 50ml deionized water with filter cake pulp, filtration and with filtration cakes torrefaction with analyze.The heavy 3.98g of cake represents productive rate 61%, contains to be less than unwanted α-anomer of 1%.
At large narrate the present invention, comprised its embodiment preferred.Yet, should be appreciated that consider content of the present invention, only otherwise exceed the scope and spirit of the present invention of defined in the claim of back, one of skill in the art can change and/or improves the present invention.
Press the statement of PCTA19 (1) bar
Sent application form international search report on February 8th, 1996 about this title.According to the regulation of the 19th of Patent Cooperation Treaty, the applicant proposes at this, replaces the 15th of Original submission international application book with replacing page or leaf (P15).
Increase claim 8 and be used for regulation another embodiment of the invention.The 9th page of this specification sheets, the capable support that can find new claim of 10-26.
According to the regulation of 19 (2) bars, can't permit the international application disclosure that exceeds submission in the modification.Application request with the content of the replacement page or leaf of the 15th page of international application as original submission case.
Claims
Modification according to the 19th of treaty
1. purify and separate the method that is rich in β-anomeric nucleosides for one kind, this method comprises:
A) provide a kind of R that in high boiling solvent, contains " with as shown in the formula the mixture that is rich in β-anomeric nucleosides:
Wherein each X is independently selected from hydroxyl protecting group, R ' be as shown in the formula nuclear alkali:
Wherein W is an amino protecting group, and R " be as shown in the formula nuclear alkali,
Wherein W ' is amino protecting group or hydrogen;
B) with a kind of this mixture of organic solvent diluting that is selected from ethers, ester class and nitrile;
C) reaction mixture with dilution adds in the aqueous acids, and
D) keep so acidic mixture of preparation under 70-100 ℃ temperature, W is that the formula IB product of W ' is precipitated out in formula.
2. the process of claim 1 wherein with acetonitrile, ethyl acetate and tetrahydrofuran (THF) diluted reaction mixture.
3. the method for claim 2 is wherein used the dilution in acetonitrile reaction mixture.
4. the process of claim 1 wherein that aqueous acids is the hydrochloric acid of 1～6N.
5. the acidic mixture that the process of claim 1 wherein is stirred, and product is precipitated out simultaneously.
6. the method for claim 1 also comprises the formula IB product deprotection that will purify, produces a kind of nucleosides, promptly 1-(2 '-deoxidation-2 ', 2 '-two fluoro-D-ribofuranosyls-4-aminopyrimidine-2-ketone.
7. basic as front embodiment described purification be rich in the method for β-anomeric nucleosides.
8. basic as front embodiment described purification be rich in the method for β-anomer nucleosides, it also comprises:
(e) reclaiming R " recycles.
Claims (7)
1. purify and separate the method that is rich in β-anomeric nucleosides for one kind, this method comprises:
A) provide a kind of R that in high boiling solvent, contains " with as shown in the formula the mixture that is rich in β-anomeric nucleosides:
Wherein each X is independently selected from hydroxyl protecting group, R ' be as shown in the formula nuclear alkali:
Wherein W is an amino protecting group, and R " be as shown in the formula nuclear alkali,
Wherein W ' is amino protecting group or hydrogen;
B) with a kind of this mixture of organic solvent diluting that is selected from ethers, ester class and nitrile;
C) reaction mixture with dilution adds in the aqueous acids, and
D) keep so acidic mixture of preparation under 70-100 ℃ temperature, W is that the formula IB product of W ' is precipitated out in formula.
2. the process of claim 1 wherein with acetonitrile, ethyl acetate and tetrahydrofuran (THF) diluted reaction mixture.
3. the method for claim 2 is wherein used the dilution in acetonitrile reaction mixture.
4. the process of claim 1 wherein that aqueous acids is the hydrochloric acid of 1～6N.
5. the acidic mixture that the process of claim 1 wherein is stirred, and product is precipitated out simultaneously.
6. the method for claim 1 also comprises the formula IB product deprotection that will purify, produces a kind of nucleosides, promptly 1-(2 '-deoxidation-2 ', 2 '-two fluoro-D-ribofuranosyls-4-aminopyrimidine-2-ketone.
7. basic as front embodiment described purification be rich in the method for β-anomeric nucleosides.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/340,972 | 1994-11-17 | ||
| US08/340,972 US5606048A (en) | 1992-06-22 | 1994-11-17 | Stereoselective glycosylation process for preparing 2'-Deoxy-2', 2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1165519A true CN1165519A (en) | 1997-11-19 |
| CN1044119C CN1044119C (en) | 1999-07-14 |
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|---|---|---|---|
| CN95196272A Expired - Fee Related CN1044119C (en) | 1994-11-17 | 1995-11-01 | Process for purifying and isolating 2'-deoxy-2'-2'-difluoronucleosides |
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| US6326507B1 (en) | 1998-06-19 | 2001-12-04 | Trustees Of Dartmouth College | Therapeutic compounds and methods of use |
| MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
| CA2410579C (en) | 2000-05-26 | 2010-04-20 | Jean-Pierre Sommadossi | Methods and compositions for treating flaviviruses and pestiviruses |
| US7435755B2 (en) * | 2000-11-28 | 2008-10-14 | The Trustees Of Dartmouth College | CDDO-compounds and combination therapies thereof |
| WO2003059339A1 (en) * | 2002-01-15 | 2003-07-24 | Trustees Of Dartmouth College | Tricyclic-bis-enone derivatives and methods of use thereof |
| CN101172993A (en) * | 2002-06-28 | 2008-05-07 | 埃迪尼克斯(开曼)有限公司 | 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
| US7608600B2 (en) * | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
| JP2005533824A (en) * | 2002-06-28 | 2005-11-10 | イデニクス（ケイマン）リミテツド | 2'-C-methyl-3'-OL-valine ester ribofuranosyl cytidine for the treatment of Flaviviridae infections |
| AU2003291726A1 (en) * | 2002-11-04 | 2004-06-07 | Xenoport, Inc. | Gemcitabine prodrugs, pharmaceutical compositions and uses thereof |
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